Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, dementia, and psychiatric symptoms. As the disease progresses, concentration and short-term memory diminish and involuntary movements of the head, trunk, and limbs increase. Walking, speaking, and swallowing abilities deteriorate. Eventual death results from complications such as choking, infection, or heart failure.
The causative mutation is a CAG trinucleotide expansion in exon 1 of the Huntington (Htt) gene (Huntington's Disease Collaborative Research Group (1993). Normal chromosomes have 35 or fewer CAG repeats in the N-terminal region, whereas HD is associated with 36 or more repeats. The expanded CAG repeats are translated into polyglutamine residues (polyQ) in the Htt protein. When the number of CAG repeats exceeds 36, specific degeneration of several brain areas (especially in the striatum) occurs. Formation of Htt aggregates and alteration of overall gene expression profiles have also been reported in peripheral tissues including blood cells, the liver, and kidney (Borovecki, F. et al. (2005); Panov, et al. (2005); Ishiguro, et al. (2001)). Accumulating evidence from different laboratories suggests that mutant Htt forms aggregates and causes aberrant protein-protein interactions (Bates, G. (2003)). Although a few therapeutic agents with moderate effects have been reported, there is a continuing need in the art for effective treatments for HD.